The study investigates the role of the P2X7 receptor (P2X7R) in the post-translational processing of interleukin (IL)-1β. P2X7R-deficient mice were generated to explore this function. Macrophages from these mice respond to lipopolysaccharide (LPS) and produce cyclooxygenase-2 (Cox-2) and pro-IL-1β levels comparable to wild-type cells. However, in response to ATP, pro-IL-1β produced by P2X7R−/− cells is not externalized or activated by caspase-1. Nigricin, an alternative secretion stimulus, promotes the release of mature IL-1β from P2X7R−/− macrophages. In vitro, both wild-type and P2X7R−/− animals show increased peritoneal lavage IL-6 levels after LPS injection but no detectable IL-1. ATP injection to wild-type animals increases IL-1 production, which leads to additional IL-6 production, while similar increases do not occur in ATP-treated, LPS-primed P2X7R−/− animals. The absence of P2X7R results in impaired cytokine signaling cascades in P2X7R-deficient animals. These findings demonstrate that P2X7R activation can provide a signal leading to the maturation and release of IL-1β and the initiation of a cytokine cascade.The study investigates the role of the P2X7 receptor (P2X7R) in the post-translational processing of interleukin (IL)-1β. P2X7R-deficient mice were generated to explore this function. Macrophages from these mice respond to lipopolysaccharide (LPS) and produce cyclooxygenase-2 (Cox-2) and pro-IL-1β levels comparable to wild-type cells. However, in response to ATP, pro-IL-1β produced by P2X7R−/− cells is not externalized or activated by caspase-1. Nigricin, an alternative secretion stimulus, promotes the release of mature IL-1β from P2X7R−/− macrophages. In vitro, both wild-type and P2X7R−/− animals show increased peritoneal lavage IL-6 levels after LPS injection but no detectable IL-1. ATP injection to wild-type animals increases IL-1 production, which leads to additional IL-6 production, while similar increases do not occur in ATP-treated, LPS-primed P2X7R−/− animals. The absence of P2X7R results in impaired cytokine signaling cascades in P2X7R-deficient animals. These findings demonstrate that P2X7R activation can provide a signal leading to the maturation and release of IL-1β and the initiation of a cytokine cascade.